The effectiveness of many drugs in their therapeutic usage frequently depends on their rate of oxidative metabolism by a unique electron transport system associated with the microsomal fraction of many tissues. Considerable knowledge has been gained about the basic biochemical reactions catalyzed by the terminal oxidase, cytochrome P-450, and the electron transfer flavoprotein, NADPH-cytochrome P-450 reductase. It is proposed to delineate the physical and chemical characteristics of key intermediates formed during the reaction of the substrate complex of cytochrome P-450 with oxygen and organic hydroperoxides, including an evaluation of the role of membrane organization and the heterogeneity of different types and forms of cytochrome P-450. These studies are directed to furthering our understanding of the regulation of drug metabolism and the factors modifying drug-drug interaction and the interplay which might exist during the metabolic conversion of other xenobiotics such as ethanol, polycyclic hydrocarbons and fatty acids. Principal emphasis will be directed to evaluating the functional differences of various types of cytochrome P-450 and their distribution in different organs and cell types of the human body. Characterization of functionally inactive complexes of reduced cytochrome P-450 with products of metabolism of some drugs and the in vivo and in vitro influences on the rate of metabolism of other drugs will be further examined. The broad spectrum of reactions catalyzed by this mixed function oxidase and the central role of intra-cellular metabolic intermediates, notably reduced pyridine nucleotides, will be examined to assess the metabolic interrelationships critical for the regulation of drug detoxification.